Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity

Attention-deficit hyperactivity disorder (ADHD) affects approximately 3%-5% of children in the United States. In the current psychiatric nomenclature, ADHD comprises three subtypes: inattentive, hyperactive-impulsive, and combined. In this study, we used four analytic strategies to examine the association and linkage of the dopamine transporter gene (DAT1) and ADHD. Our sample included 122 children referred to psychiatric clinics for behavioral and learning problems that included but were not limited to ADHD, as well as their parents and siblings. Within-family analyses of linkage disequilibrium, using the transmission disequilibrium test (TDT), confirmed the 480-bp allele as the high-risk allele. In between-family association analyses, levels of hyperactive-impulsive symptoms but not inattentive symptoms were related to the number of DAT1 high-risk alleles. Siblings discordant for the number of DAT1 high-risk alleles differed markedly in their levels of both hyperactive-impulsive and inattentive symptoms, such that the sibling with the higher number of high-risk alleles had much higher symptom levels. Within-family analyses of linkage disequilibrium, using the TDT, suggested association and linkage of ADHD with DAT1 and that this relation was especially strong with the combined but not the inattentive subtype. The relation of DAT1 to ADHD increased monotonically, from low to medium to high levels of symptom severity. Our results replicate and extend previous findings of the association between the DAT1 gene and childhood ADHD. This represents one of the first replicated relations of a candidate gene and a psychiatric disorder in children.     

Concordance of self- and informant ratings of adults' current and childhood attention-deficit/hyperactivity disorder symptoms.

Self-informant rating concordance for attention-deficit/hyperactivity disorder (ADHD) symptoms was assessed in 281 adults at the subscale (Inattention, Hyperactivity-Impulsivity) and individual symptom levels. Potential demographic, diagnostic, and informant identity moderators were also investigated. Concordance levels were similar for current and childhood symptoms. Although moderate positive correlations were found between self- and informant ratings on both subscales, informants endorsed more significant inattentive symptom severity. Kappa coefficients were variable, suggesting low concordance for certain symptoms. Sex and ADHD diagnosis moderated concordance, although effect sizes were small. These results have implications for the use of behavior rating scales in diagnosing ADHD, raise questions about the validity of self- and informant ratings, and support the need to investigate individual differences variables that may impact concordance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Visual search performance in children rated as good or poor attenders: The differential impact of DAT1 genotype, IQ, and chronological age.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by poor attention to detail, poor attention maintenance, and variability throughout task performance. The authors used a quantitative trait loci approach to assess the association between the dopamine transporter (DAT1) high-risk genotype, cognitive performance (visual search and vigilance), and ADHD symptoms in a community sample of boys 6-11 years of age. The potential confounding effects of IQ and chronological age were also investigated. Results demonstrate that accuracy in target detection, not speed, distinguishes poor attenders from good attenders. The authors speculate that the measure of performance (e.g., time and false alarms) may be critical in detecting attentional weaknesses. In contrast, DAT1 gene, known to be associated with the behavioral symptoms of ADHD, was unrelated to visual search or vigilance performance, although it was related to ADHD symptoms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Retrospective ratings of ADHD symptoms made at young adulthood by clinic-referred boys with ADHD-related problems, their brothers without ADHD, and control participants.

Retrospective childhood attention-deficit/hyperactivity disorder (ADHD) symptoms are required to diagnosis adult ADHD, but the validity of self-rated symptoms across time is questionable. Here, boys with ADHD-related problems, their brothers without ADHD, and former schoolmates rated themselves during young adulthood for ages 9, 14, and 19. Brothers rated probands retrospectively at the same ages. The young adults referred as children for ADHD (a) acknowledged childhood symptoms; (b) described improvement over time; (c) did not differ from brothers or controls on most self-ratings of young adult symptoms; (d) rated themselves as more symptomatic at age 9, but less symptomatic at age 19, than their brothers rated them; and (e) agreed only to some degree with brothers' ratings of probands' aggression (median correlation = .22). Probands' ratings showed limited agreement with judges' symptom ratings (median correlation = .16) and young adult follow-up examiners' ratings (median correlation = .14). These findings are not accounted for solely by changes in informants, nor by the course of ADHD psychopathology. They suggest some stability but limited internal consistency and validity for retrospective ADHD ratings by probands and brothers. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Absence of anti-envelope antibodies and clearance of hepatitis C virus in a cohort of Irish women infected in 1977

Neuroleptic drugs have a high affinity for the dopamine D2 receptor (DRD2); therefore DRD2 is thought to be a candidate gene for schizophrenia. Arinami et al. have reported a positive association between schizophrenia and the Cys311 variant of the DRD2 gene. We determined the allele frequency of this polymorphism in 78 Okinawan schizophrenic patients and 112 control subjects. The patients and controls did not differ significantly in allele frequencies of Cys311.     

Association study between schizophrenia and dopamine D3 receptor gene polymorphism

Crocq et al. [1992: J Med Genet 29:858-860] reported the existence of an association between schizophrenia and homozygosity of a BalI polymorphism in the first exon of the dopamine D3 receptor (DRD3) gene. In response to this report, further studies were conducted; however, these studies yielded conflicting results. In the present study, we examined 100 unrelated Japanese schizophrenics and 100 normal controls to determine any association between this polymorphism and schizophrenia. Results suggest that neither allele nor genotype frequencies of the DRD3 gene in the schizophrenics as a whole are significantly different from those of the controls. Further, we found no association between any allele or genotype and any clinical subtype based on family history of schizophrenia and age-at-onset. A significantly high frequency of homozygosity of a dopamine D3 receptor gene allele was not observed in the schizophrenics as a whole, or in clinical subtypes. Our results suggest that an association between the dopamine D3 receptor gene and schizophrenia is unlikely to exist.     

Atrial adipofibrosis in a dog

Recent studies in healthy controls suggest an association between novelty-seeking (NS) and the dopamine D4 receptor (DRD4) gene. In this study, we further investigated the relationship between genes implicated in dopamine as well as serotonin neurotransmission and personality traits in bipolar (BP) disorder. Scores on the Tridimensional Personality Questionnaire were examined in 37 recovered Research Diagnostic Criteria-diagnosed BP patients genotyped for DRD3, DRD4, and serotonin 2A receptor (5HTR2a) polymorphisms. Carriers of DRD3 allele 1 showed significantly lower NS values compared to patients without this allele. Scores on NS and on harm-avoidance were not related to DRD4 or 5HTR2a polymorphisms. These preliminary results suggest a role for D3 receptor in NS expression in BP patients.     

Assessing symptoms of attention deficit hyperactivity disorder in children and adults: Which is more valid?

The assessment of attention deficit hyperactivity disorder (ADHD) in adults has been a source of controversy. The authors tested competing ideas by evaluating familial transmission among adult and nonadult relatives of ADHD children. They analyzed ADHD symptom data collected by structured interviews from the members of 280 ADHD and 242 non-ADHD families. For both past and current symptoms, both the boys' and girls' families showed significantly more familial aggregation for adult relatives than for nonadult relatives. The results were similar for inattentive and hyperactive-impulsive symptoms and for relatives with and without psychiatric comorbidity. The results provide further evidence for the validity of adult ADHD and support the intriguing idea that, from a familial perspective, the assessment of ADHD may be more valid in adults than in children. They do not support the idea that parents of ADHD children are biased to report ADHD symptoms in themselves because of their exposure to an ADHD child. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

An association between the DAT1 polymorphism and smoking behavior in young adults from the national longitudinal study of adolescent health.

Associations between smoking behavior and polymorphisms in the dopaminergic genes (DAT1 and DRD2) were tested by using within- and between-family measures of allelic transmission in 2,448 young adults from the National Longitudinal Study of Adolescent Health. The 9-repeat allele of the dopamine transporter gene polymorphism (DAT1) was inversely associated with smoking in samples that included all subjects and only those who had initiated smoking, accounting for approximately 1% of the variance. Never smokers and current nonsmokers had an excess transmission of the 9-repeat allele compared with regular smokers, suggesting a protective effect of the 9-repeat allele, which is hypothesized to alter synaptic dopamine levels. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Polymorphisms of dopamine receptor and transporter genes and Parkinson's disease

Disturbances of the dopamine system are involved in the pathogenesis of idiopathic Parkinson's disease (PD). Although genetic factors may play a role in the etiology of PD, there is little direct evidence implicating a specific gene. We conducted a study to test the hypothesis that allelic variations of the dopamine receptors (D2, D3, D4) and the dopamine transporter (DAT) contribute to the susceptibility to PD. Association analyses of 70 Japanese PD patients and the same number of age-matched controls did not reveal any association between alleles of the D2, D3 or D4 receptor genes or the DAT gene and PD. Thus, our results suggest that factor(s) other than allelic variations of these key proteins in the dopamine system contribute to the susceptibility to PD.     

Neurotransmission-related genetic polymorphisms, negative affectivity traits, and gender predict tobacco abstinence symptoms across 44 days with and without nicotine patch.

Genetic and personality trait moderators of tobacco abstinence–symptom trajectories were assessed in a highly controlled study. Based on evidence suggesting their importance in stress reactivity and smoking, moderators studied were serotonin transporter gene (5-HTTLPR) and dopamine D2 receptor gene (DRD2) polymorphisms and personality traits related to negative affect (NA). Smokers were randomly assigned to quit smoking with nicotine or placebo patches. Financial incentives resulted in 80% verified abstinence across the 44-day study. Individuals with 1 or 2 short alleles of 5-HTTLPR (S carriers) experienced larger increases in NA symptoms than did those without a short allele. Nicotine replacement therapy (NRT) alleviated anxiety only in S carriers. NRT reduced NA to a greater extent in DRD2 A1 carriers than in A2A2 individuals during the 1st 2 weeks of treatment (when on the 21-mg patch); however, A1 carriers experienced a renewal of NA symptoms when switched to the 7-mg patch and when off the patch, while A2A2 individuals continued to benefit from NRT. The results suggest that the effects of genotype and treatment may vary across different durations of abstinence, treatment doses, and genotypes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Polymorphisms in dopamine system genes are associated with individual differences in attention in infancy.

Knowledge about the functional status of the frontal cortex in infancy is limited. This study investigated the effects of polymorphisms in four dopamine system genes on performance in a task developed to assess such functioning, the Freeze-Frame task, at 9 months of age. Polymorphisms in the catechol-O-methyltransferase (COMT) and the dopamine D4 receptor (DRD4) genes are likely to impact directly on the functioning of the frontal cortex, whereas polymorphisms in the dopamine D2 receptor (DRD2) and dopamine transporter (DAT1) genes might influence frontal cortex functioning indirectly via strong frontostriatal connections. A significant effect of the COMT valine1??methionine (Val158Met) polymorphism was found. Infants with the Met/Met genotype were significantly less distractible than infants with the Val/Val genotype in Freeze-Frame trials presenting an engaging central stimulus. In addition, there was an interaction with the DAT1 3` variable number of tandem repeats polymorphism; the COMT effect was present only in infants who did not have two copies of the DAT1 10-repeat allele. These findings indicate that dopaminergic polymorphisms affect selective aspects of attention as early as infancy and further validate the Freeze-Frame task as a frontal cortex task. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopamine receptor genetic variation, psychosis, and aggression in Alzheimer disease

OBJECTIVE: To examine if selected polymorphisms in the dopamine receptor genes DRD1, DRD2, DRD3, and DRD4 are associated with the presence of psychosis or aggressive behavior in patients with Alzheimer disease (AD). DESIGN: A cohort of patients with AD were longitudinally evaluated for behavioral symptoms and classified with regard to the presence of psychotic symptoms and physical aggression. SETTING: Alzheimer's Disease Research Center. PATIENTS: Two hundred seventy-five elderly outpatients diagnosed as having probable AD. RESULTS: Among white patients, psychosis and aggression were both significantly more frequent in DRD1 B2/B2 homozygotes (P < .02), while psychosis was significantly more frequent in DRD3 1/1 or 2/2 homozygotes (P < .05). The joint risk for psychosis due to the DRD1 and DRD3 polymorphisms exceeded the risks due to either locus alone, suggesting an interaction. Neither the DRD2 S311C polymorphism nor the presence of long alleles for the DRD4 exon III repeat sequence was associated with psychosis or aggression. CONCLUSIONS: Genetic variation in DRD1 and DRD3 genes may act to modify the course of AD, predisposing to the development of psychotic or aggressive symptoms. Confirmation in other samples of patients with AD is required.     

Axis I and II comorbidity in adults with ADHD.

Ongoing debate over the validity of the attention-deficit/hyperactivity disorder (ADHD) construct in adulthood is fueled in part by uncertainty regarding implications of potentially extensive yet incompletely described comorbid Axis I and II psychopathology. Three hundred sixty-three adults ages 18 to 37 completed semistructured clinical interviews; informants were also interviewed, and best estimate diagnoses were obtained. Results were as follows: First, ADHD combined type (ADHD-C) had an excess of externalizing and internalizing Axis I disorders, suggesting a gradient-of-severity relationship between it and ADHD inattentive type (ADHD-I). Second, ADHD-C and ADHD-I did not differ in frequency of Axis II disorders. Third, however, ADHD overall was associated with increased rates of Axis II disorders, compared with rates in non-ADHD control participants, including both Cluster B (primarily borderline personality disorder) and Cluster C disorders. Fourth, ADHD incrementally accounted for clinician-rated global assessment of functioning scores above and beyond comorbid conditions or symptoms on either Axis I or Axis II. Results further inform nosology of ADHD in adults. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity

The mechanism by which psychostimulants act as calming agents in humans with attention-deficit hyperactivity disorder (ADHD) or hyperkinetic disorder is currently unknown. Mice lacking the gene encoding the plasma membrane dopamine transporter (DAT) have elevated dopaminergic tone and are hyperactive. This activity was exacerbated by exposure to a novel environment. Additionally, these mice were impaired in spatial cognitive function, and they showed a decrease in locomotion in response to psychostimulants. This paradoxical calming effect of psychostimulants depended on serotonergic neurotransmission. The parallels between the DAT knockout mice and individuals with ADHD suggest that common mechanisms may underlie some of their behaviors and responses to psychostimulants.     

Masculinized finger-length ratios of boys, but not girls, are associated with attention-deficit/hyperactivity disorder.

Gonadal hormones may exert permanent organizational effects on sexually dimorphic finger-length ratios and sexually dimorphic behavior expressed in childhood attention deficit- hyperactivity disorder (ADHD). This study extended recent work examining associations between finger-length ratios (specifically, 2D:4D) and ADHD in a well-characterized, clinically diagnosed, community-recruited sample of boys and girls. A multistage, diagnostic procedure was utilized to identify 113 children with ADHD and 137 non-ADHD comparison children. Right-hand digit ratios showed significant mean differences by gender, as well as associations with ADHD diagnosis. Boys with ADHD had more masculinized digit ratios than control-group boys. More masculine right 2D:4D and 3D:4D ratios were correlated with parent- and teacher-rated inattentive and hyperactive-impulsive symptoms in boys but not in girls. Masculinized finger-length ratios were associated with hyperactive-impulsive and oppositional- defiant symptoms, but associations were largest with symptoms of inattention. It is concluded that prenatal, organizational effects of gonadal hormones may play a role in the development of ADHD and contribute to explaining sex differences in the prevalence rates of this childhood disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Codon usage in Taenia species

BACKGROUND: Evidence from family and twin studies suggests a genetic contribution to the etiology of anorexia nervosa. Different genes could contribute to the vulnerability to anorexia nervosa, but dopamine could be more specifically implicated in anorexia nervosa because of pharmacologic, endocrine, and neurobiological specificities. The dopamine receptor D3 (DRD3) may be of additional interest, since it is specifically located in the limbic area, an area implicated in reward and reinforcement behavior. METHODS: We performed an association study between 39 patients with severe (requiring hospitalization and with young age at onset) anorexia nervosa (DSM-III-R), and 42 controls, with the Bal I polymorphism in exon I of the DRD3 gene. RESULTS: There was no significant difference between patients with anorexia nervosa and controls in allele frequencies or genotype count. The association was still negative between subgroups separated according to family history of anorexia nervosa or comorbid mood disorders. CONCLUSIONS: Despite the fact that the number of patients tested is small, there is good evidence that the Bal I DRD3 polymorphism does not play a major role in the genetic component of anorexia nervosa. It would be useful to test polymorphisms of the other genes coding for dopamine receptors.     

Prospective follow-up of girls with attention-deficit/hyperactivity disorder into adolescence: Evidence for continuing cross-domain impairment.

The authors performed 5-year prospective follow-up (retention rate = 92%) with an ethnically diverse sample of girls, aged 11-18 years, who had been diagnosed in childhood with attention-deficit/ hyperactivity disorder (ADHD; N = 140) and a matched comparison group (N = 88). Hyperactive-impulsive symptoms were more likely to abate than inattentive symptoms. Across multiple domains of symptoms and functional impairment, girls with ADHD continued to display deficits of moderate to large effect size in relation to the comparison girls, but few differences emerged between the inattentive versus combined types. Follow-up effects withstood statistical control of crucial covariates for most outcomes, meaning that there were specific effects of childhood ADHD on follow-up status; in other instances, baseline disruptive disorders accounted for adolescent effects. For outcomes identical at baseline and follow-up, girls with ADHD showed more improvement across time than comparison girls (except for math achievement). Overall, ADHD in girls portends continuing impairment 5 years after childhood ascertainment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interactions between early parenting and a polymorphism of the child's dopamine transporter gene in predicting future child conduct disorder symptoms.

Mounting evidence suggests that genetic risks for mental disorders often interact with the social environment, but most studies still ignore environmental moderation of genetic influences. The authors tested interactions between maternal parenting and the variable number tandem repeat (VNTR) polymorphism in the 3′ untranslated region of the dopamine transporter gene in the child to increase understanding of gene–environment interactions involving early parenting. Participants were part of a 9-year longitudinal study of 4- to 6-year-old children who met criteria for attention-deficit/hyperactivity disorder (ADHD) and demographically matched controls. Maternal parenting was observed during standard mother–child interactions in Wave 1. The child's conduct disorder (CD) symptoms 5–8 years later were measured using separate structured diagnostic interviews of the mother and youth. Controlling for ADHD symptoms and child disruptive behavior during the mother–child interaction, there was a significant inverse relation between levels of both positive and negative parenting at 4–6 years and the number of later CD symptoms, but primarily among children with 2 copies of the 9-repeat allele of the VNTR. The significant interaction with negative parenting was replicated in parent and youth reports of CD symptoms separately. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Parallel forms of the IJR Behavior Checklist for parents, teachers, and clinicians.

It is suggested that the use of multiple informants in diagnostic evaluations exacerbates a major difficulty in the use of symptom checklists—establishing replicable syndromes across data sources. The present study attempted to develop symptom scales for 3 parallel checklists for 3 types of informants to maximize the comparability of data across informants without sacrificing all of the distinctiveness of different evaluators' frames of reference. Separate cluster analyses of 450 parent checklists, 300 teacher checklists, and 299 clinician checklists yielded 9 syndromes that were comparable across all 3 informants, 4 that were identifiable in the data from only 2 informants, and 5 that were unique to the data from a single type of informant. (53 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)